CB1 receptor knockout mice are hyporesponsive to the behavior-stimulating actions of d-amphetamine: Role of mGlu5 receptors Eleni T. Tzavara a,b, ⁎ ,1 , Aldemar Degroot a,1,2 , Mark R. Wade a , Richard J. Davis a , George G. Nomikos a,3 a Eli Lilly & Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285-0510, United States b INSERM U-513, Université Pierre et Marie Curie, 9 quai St Bernard, 75005, Paris, France Received 16 August 2008; received in revised form 6 October 2008; accepted 12 November 2008 KEYWORDS CB1 receptor; mGluR5; d-amphetamine; MK-801; Locomotor activity; Dopamine; Microdialysis Abstract Blockade of the cannabinoid CB1 receptors (CB1R) has been shown to reduce psychostimulant- induced hyperactivity, an effect that we sought to further characterize here. The CB1R antagonist SR141716A dose-dependently decreased d-amphetamine-induced hyperactivity. Also, d-amphetamine-induced hyperlocomotion was reduced in CB1R knockout (KO) mice. However, CB1R KO and wild-type mice showed a similar d-amphetamine-induced increase in nucleus accumbens DA release. Hence, we investigated whether CB1R antagonism/invalidation reduces d-amphetamine-induced hyperlocomotion through a mechanism involving changes in glutamatergic neurotransmission. Blockade of metabotropic-glutamate-receptors-5 (mGluR5) with MPEP, but not blockade of N-methyl-D-aspartate-receptors (NMDA) with MK-801, restored to a great extent the blunted d-amphetamine-induced hyperlocomotion seen after CB1R antagonism/invalidation. Thus, hyporesponsiveness to the psychostimulant effects of d-amphetamine as a result of CB1R antagonism/invalidation is not due to an ensuing decrease in d-amphetamine-induced DA release in the nucleus accumbens, but rather due to a hyperglutamatergic state and facilitation of glutamatergic neurotransmission at the mGlu5, but not NMDA, receptors. © 2008 Elsevier B.V. and ECNP. All rights reserved. 1. Introduction The cannabinoid system interacts widely with other neuro- transmitter systems (including the dopaminergic, cholinergic and glutamatergic systems) at the presynaptic or postsynaptic levels to regulate brain function. In particular, cannabinoids have been implicated in cognitive function, mood regulation and in neuroadaptative and behavioral responses to addictive ⁎ Corresponding author. INSERM U-513, Université Pierre et Marie Curie, 9 quai St Bernard, 75005, Paris, France. E-mail address: eleni.tzavara@snv.jussieu.fr (E.T. Tzavara). 1 These authors equally contributed to this work. 2 Present address: Astellas Pharma Inc, Exploratory Development Department, Leiderdorp, the Netherlands. 3 Present address: Takeda Global Research & Development Center Inc, Clinical Neuroscience, Lake Forest, IL 60045, United States. 0924-977X/$ - see front matter © 2008 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2008.11.003 www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2009) 19, 196–204